Valosin-containing protein gene mutations: clinical and neuropathologic features

Area of Science:

• Genetics
• Neurology
• Cell Biology

Background:

• Hereditary inclusion body myopathy (IBMPFD) with Paget disease of bone (PDB) and frontotemporal dementia (FTD) is a rare autosomal dominant disorder.
• Missense mutations in the valosin-containing protein (VCP) gene are linked to IBMPFD.
• VCP plays a critical role in protein degradation and endoplasmic reticulum stress response.

Purpose of the Study:

• Investigate the clinical features of IBMPFD associated with VCP mutations.
• Examine the histopathological consequences of VCP mutations in affected tissues.
• Determine the role of VCP mutations in the pathogenesis of FTD and PDB.

Main Methods:

• Clinical assessment of two families with VCP R93C and R155C mutations.
• Histopathological examination of brain, muscle, bone, and liver tissues from three subjects with the R155C mutation.
• Biochemical analysis to assess VCP protein function.

Main Results:

• Frontotemporal dementia (FTD) was highly prevalent (100% in Family F1, 70% in Family F2), exceeding previously reported rates.
• Paget disease of bone (PDB) was an inconstant clinical feature.
• Histopathology and biochemical data indicated that the VCP R155C mutation impairs VCP function, causing ubiquitinated protein accumulation.

Conclusions:

• VCP mutations are associated with IBMPFD, with FTD being a prominent symptom.
• The R155C mutation disrupts VCP function, leading to cellular ubiquitinated protein accumulation.
• IBMPFD represents a class of genetic disorders linked to the ubiquitin-proteasome system.